hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in western countries. Bile acid sequestrants seem to be moderately effective as antihypercholesterolemic agents but they must be consumed in large quantites, i.e., several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof. For example, simvastatin wherein the 8-acyl moiety is 2,2-dimethylbutyryloxy is an even more potent HMBG-CoA reductase inhibitor than lovastatin. Simvastatin is now commercially available as ZOCOR.RTM. in some markets.
The triol acid (I), produced by the process disclosed herein, may after lactonization to its corresponding diol lactone (II), serve as a starting material for the formation of simvastatin and other 8-ester analogs and derivatives containing the polyhydronaphthyl moiety and which function as HMG-CoA reductase inhibitors.
The diol lactone (II) noted above has been produced by fermentation of Monascus ruber as described by Endo et al, published Japanese Patent Appln. 86-13798 (1986). A more recent publication by Endo, J. Antibiotics, 39, 1670 (1989) discloses various strains of Monascus ruber which yield mevinolin (lovastatin) and triol acid (I). Furthermore triol acid (I) and its corresponding diol lactone (II) have been produced by chemical hydrolysis of the 8-(.alpha.-methylbutyryloxy) group from lovastatin.
However, there is no teaching or suggestion in the art for the production of triol acid (I) employing a culture of Aspergillus terreus and forming the triol acid in high yield with a minimum production of triol acid related side products. Indeed there is no teaching or suggestion in the prior art that triol acid (I) can be formed, by any microbe, in high yield with a minimum production of triol acid related side products. As noted it is a significant advantage of the present invention that these, difficult to separate, triol acid related side products are formed in very low amounts.